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1.
FASEB J ; 35(9): e21853, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34416038

RESUMO

We highlight the ability of the tuberculosis (TB) causing bacterial pathogen, Mycobacterium tuberculosis (Mtb), to induce key characteristics that are associated with established IARC classified Group 1 and Group 2A carcinogenic agents. There is sufficient evidence from epidemiological case-control, cohort and meta-analysis studies of increased lung cancer (LC) risk in pre-existing/active/old TB cases. Similar to carcinogens and other pathogenic infectious agents, exposure to aerosol-containing Mtb sprays in mice produce malignant transformation of cells that result in squamous cell carcinoma. Convincing, mechanistic data show several characteristics shared between TB and LC which include chronic inflammation, genomic instability and replicative immortality, just to name a few cancer hallmarks. These hallmarks of cancer may serve as precursors to malignant transformation. Together, these findings form the basis of our postulate that Mtb is a complete human pulmonary carcinogen. We also discuss how Mtb may act as both an initiating agent and promoter of tumor growth. Forthcoming experimental studies will not only serve as proof-of-concept but will also pivot our understanding of how to manage/treat TB cases as well as offer solutions to clinical conundrums of TB lesions masquerading as tumors. Clinical validation of our concept may also help pave the way for next generation personalized medicine for the management of pulmonary TB/cancer particularly for cases that are not responding well to conventional chemotherapy or TB drugs.


Assuntos
Transformação Celular Neoplásica , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/microbiologia , Pulmão/microbiologia , Pulmão/patologia , Mycobacterium tuberculosis/patogenicidade , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/microbiologia , Adolescente , Adulto , Idoso , Células Epiteliais Alveolares/citologia , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Carcinógenos , Transformação Celular Neoplásica/genética , Criança , Estudos de Coortes , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Mycobacterium tuberculosis/genética , Metástase Neoplásica/genética , Células-Tronco Neoplásicas/patologia , Fatores de Risco , Tuberculose Pulmonar/patologia , Adulto Jovem
2.
Nat Commun ; 12(1): 4671, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34344863

RESUMO

Triple negative breast cancer (TNBC) remains challenging because of heterogeneous responses to chemotherapy. Incomplete response is associated with a greater risk of metastatic progression. Therefore, treatments that target chemotherapy-resistant TNBC and enhance chemosensitivity would improve outcomes for these high-risk patients. Breast cancer stem cell-like cells (BCSCs) have been proposed to represent a chemotherapy-resistant subpopulation responsible for tumor initiation, progression and metastases. Targeting this population could lead to improved TNBC disease control. Here, we describe a novel multi-kinase inhibitor, 108600, that targets the TNBC BCSC population. 108600 treatment suppresses growth, colony and mammosphere forming capacity of BCSCs and induces G2M arrest and apoptosis of TNBC cells. In vivo, 108600 treatment of mice bearing triple negative tumors results in the induction of apoptosis and overcomes chemotherapy resistance. Finally, treatment with 108600 and chemotherapy suppresses growth of pre-established TNBC metastases, providing additional support for the clinical translation of this agent to clinical trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Células-Tronco Neoplásicas/patologia , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/química , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360875

RESUMO

Single prostate stem cells can generate stem and progenitor cells to form prostaspheres in 3D culture. Using a prostasphere-based label retention assay, we recently identified keratin 13 (KRT13)-enriched prostate stem cells at single-cell resolution, distinguishing them from daughter progenitors. Herein, we characterized the epithelial cell lineage hierarchy in prostaspheres using single-cell RNA-seq analysis. Keratin profiling revealed three clusters of label-retaining prostate stem cells; cluster I represents quiescent stem cells (PSCA, CD36, SPINK1, and KRT13/23/80/78/4 enriched), while clusters II and III represent active stem and bipotent progenitor cells (KRT16/17/6 enriched). Gene set enrichment analysis revealed enrichment of stem and cancer-related pathways in cluster I. In non-label-retaining daughter progenitor cells, three clusters were identified; cluster IV represents basal progenitors (KRT5/14/6/16 enriched), while clusters V and VI represent early and late-stage luminal progenitors, respectively (KRT8/18/10 enriched). Furthermore, MetaCore analysis showed enrichment of the "cytoskeleton remodeling-keratin filaments" pathway in cancer stem-like cells from human prostate cancer specimens. Along with common keratins (KRT13/23/80/78/4) in normal stem cells, unique keratins (KRT10/19/6C/16) were enriched in cancer stem-like cells. Clarification of these keratin profiles in human prostate stem cell lineage hierarchy and cancer stem-like cells can facilitate the identification and therapeutic targeting of prostate cancer stem-like cells.


Assuntos
Queratinas/metabolismo , Células-Tronco Neoplásicas , Neoplasias da Próstata , RNA/metabolismo , Adulto , Células Cultivadas , Humanos , Masculino , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Cultura Primária de Células , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Análise de Célula Única , Adulto Jovem
4.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445562

RESUMO

Synaptonemal complex protein 3 (SCP3), a member of the Cor1 family, has been implicated in cancer progression, and therapeutic resistance, as well as cancer stem cell (CSC)-like properties. Previously, we demonstrated that SCP3 promotes these aggressive phenotypes via hyperactivation of the AKT signaling pathway; however, the underlying mechanisms responsible for SCP3-induced AKT activation remain to be elucidated. In this study, we demonstrated that the EGF-EGFR axis is the primary route through which SCP3 acts to activate AKT signaling. SCP3 triggers the EGFR-AKT pathway through transcriptional activation of EGF. Notably, neutralization of secreted EGF by its specific monoclonal antibody reversed SCP3-mediated aggressive phenotypes with a concomitant reversal of EGFR-AKT activation. In an effort to elucidate the molecular mechanisms underlying SCP3-induced transcriptional activation of EGF, we identified Jun activation domain-binding protein 1 (JAB1) as a binding partner of SCP3 using a yeast two-hybrid (Y2H) assay system, and we demonstrated that SCP3 induces EGF transcription through physical interaction with JAB1. Thus, our findings establish a firm molecular link among SCP3, EGFR, and AKT by identifying the novel roles of SCP3 in transcriptional regulation. We believe that these findings hold important implications for controlling SCP3high therapeutic-refractory cancer.


Assuntos
Complexo do Signalossomo COP9/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Fator de Crescimento Epidérmico/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Peptídeo Hidrolases/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Complexo do Signalossomo COP9/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Fator de Crescimento Epidérmico/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Peptídeo Hidrolases/genética , Fosforilação , Domínios e Motivos de Interação entre Proteínas , Transdução de Sinais , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
5.
Ann Clin Lab Sci ; 51(4): 521-528, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34452890

RESUMO

OBJECTIVE: Radioresistance-induced locoregional recurrence remains a major cause of low survival rates. However, the mechanism of treatment failure in these lung cancer patients has not been determined. In the current study, we tried to explore the potential molecular mechanism. METHODS: The fractionated irradiations were continued until the total concentration reached 80 Gy, and we established radioresistant subclones derived from A549 lines (designated as A549/R). The MTT assay, wound healing assay, transwell assay, and soft agar colony formation assay were employed to detect the proliferation, migration, invasion, and clonogenicity of the cells, respectively. Western blot and Fluorescence Activating Cell Sorter (FACS) indicated the expression of the markers. RESULTS: A549/R cells proliferated more slowly than the parental A549 cells. A significant acceleration in cell migration and invasion was revealed in A549/R cells compared with A549 cells. The expression levels of mesenchymal markers (N-cadherin, vimentin, claudin-1, and Snail) increased, while epithelial markers (E-cadherin and ß-catenin) decreased in A549/R cells. Meanwhile, the expression levels of stemness markers (Oct4, Notch1, and CD133) increased in A549/R cells, and A549/R cells showed more sphere-forming activity compared with A549 cells. CONCLUSION: Fractionated irradiation could promote epithelial-mesenchymal transition and enhance the migration, invasion, and stemness-like properties in A549 cells, elucidating the possible radioresistance mechanisms of the cancer cells.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Raios gama , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas/patologia , Células A549 , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Movimento Celular , Proliferação de Células , Fracionamento da Dose de Radiação , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/radioterapia , Invasividade Neoplásica , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos da radiação
6.
Nat Commun ; 12(1): 4413, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285210

RESUMO

Enhanced neovasculogenesis, especially vasculogenic mimicry (VM), contributes to the development of triple-negative breast cancer (TNBC). Breast tumor-initiating cells (BTICs) are involved in forming VM; however, the specific VM-forming BTIC population and the regulatory mechanisms remain undefined. We find that tumor endothelial marker 8 (TEM8) is abundantly expressed in TNBC and serves as a marker for VM-forming BTICs. Mechanistically, TEM8 increases active RhoC level and induces ROCK1-mediated phosphorylation of SMAD5, in a cascade essential for promoting stemness and VM capacity of breast cancer cells. ASB10, an estrogen receptor ERα trans-activated E3 ligase, ubiquitylates TEM8 for degradation, and its deficiency in TNBC resulted in a high homeostatic level of TEM8. In this work, we identify TEM8 as a functional marker for VM-forming BTICs in TNBC, providing a target for the development of effective therapies against TNBC targeting both BTIC self-renewal and neovasculogenesis simultaneously.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas dos Microfilamentos/metabolismo , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/patologia , Receptores de Superfície Celular/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Mama/patologia , Mama/cirurgia , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Linhagem Celular Tumoral , Autorrenovação Celular/efeitos dos fármacos , Feminino , Humanos , Mastectomia , Camundongos , Proteínas dos Microfilamentos/antagonistas & inibidores , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Receptores de Superfície Celular/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/irrigação sanguínea , Neoplasias de Mama Triplo Negativas/terapia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204510

RESUMO

Glioblastoma, a subset of aggressive brain tumors, deploy several means to increase blood vessel supply dedicated to the tumor mass. This includes typical program borrowed from embryonic development, such as vasculogenesis and sprouting angiogenesis, as well as unconventional processes, including co-option, vascular mimicry, and transdifferentiation, in which tumor cells are pro-actively engaged. However, these neo-generated vascular networks are morphologically and functionally abnormal, suggesting that the vascularization processes are rather inefficient in the tumor ecosystem. In this review, we reiterate the specificities of each neovascularization modality in glioblastoma, and, how they can be hampered mechanistically in the perspective of anti-cancer therapies.


Assuntos
Glioblastoma/metabolismo , Glioblastoma/patologia , Neovascularização Patológica/metabolismo , Animais , Biomarcadores , Comunicação Celular , Diferenciação Celular , Suscetibilidade a Doenças , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Glioblastoma/etiologia , Glioblastoma/terapia , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Tolerância a Radiação , Transdução de Sinais , Microambiente Tumoral
8.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203589

RESUMO

Pancreatic ductal adenocarcinoma is one of the deadliest tumors. This neoplasia is characterized by an important cellular and phenotypic heterogeneity. In particular, it has been shown that at least two subtypes can be found: basal-like, which presents stem-like properties, and classical. Cancer stem cells have been isolated and characterized from these tumors, showing their dependance on general and tissue-specific stem transcription factors and signaling pathways. Nevertheless, little is known about their tissue microenvironment and cell non-autonomous regulators, such as long-non-coding RNAs. (lncRNAs). In this review, we summarize the current knowledge about the positive and negative effects of lncRNAs in the stemness phenotype of pancreatic ductal adenocarcinoma cancer (PDAC).


Assuntos
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/genética , RNA Longo não Codificante/metabolismo , Adenocarcinoma/patologia , Animais , Carcinoma Ductal Pancreático/patologia , Humanos , Células-Tronco Neoplásicas/metabolismo , Neoplasias Pancreáticas/patologia , Fenótipo , RNA Longo não Codificante/genética
9.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298975

RESUMO

Previously, we showed that chemotherapy paradoxically exacerbated cancer cell colonization at the secondary site in a manner dependent on Atf3, a stress-inducible gene, in the non-cancer host cells. Here, we present evidence that this phenotype is established at an early stage of colonization within days of cancer cell arrival. Using mouse breast cancer models, we showed that, in the wild-type (WT) lung, cyclophosphamide (CTX) increased the ability of the lung to retain cancer cells in the vascular bed. Although CTX did not change the WT lung to affect cancer cell extravasation or proliferation, it changed the lung macrophage to be pro-cancer, protecting cancer cells from death. This, combined with the initial increase in cell retention, resulted in higher lung colonization in CTX-treated than control-treated mice. In the Atf3 knockout (KO) lung, CTX also increased the ability of lung to retain cancer cells. However, the CTX-treated KO macrophage was highly cytotoxic to cancer cells, resulting in no increase in lung colonization-despite the initial increase in cell retention. In summary, the status of Atf3 dictates the dichotomous activity of macrophage: pro-cancer for CTX-treated WT macrophage but anti-cancer for the KO counterpart. This dichotomy provides a mechanistic explanation for CTX to exacerbate lung colonization in the WT but not Atf3 KO lung.


Assuntos
Fator 3 Ativador da Transcrição/fisiologia , Ciclofosfamida/toxicidade , Neoplasias Pulmonares/secundário , Macrófagos/fisiologia , Neoplasias Mamárias Experimentais/genética , Metástase Neoplásica/fisiopatologia , Proteínas de Neoplasias/fisiologia , Estresse Fisiológico/genética , Macrófagos Associados a Tumor/fisiologia , Animais , Peptídeos Catiônicos Antimicrobianos/biossíntese , Peptídeos Catiônicos Antimicrobianos/genética , Linhagem Celular Tumoral , Ciclofosfamida/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes Reporter , Genótipo , Humanos , Neoplasias Pulmonares/metabolismo , Ativação de Macrófagos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Camundongos Transgênicos , Terapia Neoadjuvante/efeitos adversos , Metástase Neoplásica/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Transplante de Neoplasias/métodos , Células-Tronco Neoplásicas/patologia , Migração Transendotelial e Transepitelial , Microambiente Tumoral , Macrófagos Associados a Tumor/efeitos dos fármacos
10.
Gene ; 801: 145844, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34274471

RESUMO

In the treatment of breast cancer (BC), as an important type of cancer in women, the specific cells, called cancer stem cells (CSCs), are the reason of failure and metastasis. So, targeting CSCs can be used as a novel strategy in cancer therapy in addition to common therapeutic strategies. According to the importance of CSCs, we tried to find a correlation between stemness and metastatic characteristics of BC cells, to address whether CSCs are a potential target for cancer therapy. Here, we evaluated the NANOG inhibition by siRNA and the increase of Let-7a levels by miRNA mimic in breast cancer cells and the effects of these changes on biologic aspects like cell apoptosis, stemness and invasion. Our results showed that the inhibition of NANOG combined with Let-7a restoration contributed to significant decrease in malignant phenotypes and stemness feature of BC cells. In conclusion, these findings showed that the combination of Let-7a miRNA mimic and Nanog siRNA could be exploited as a new treatment strategy to improve the cancer therapy outcome.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , MicroRNAs/genética , Proteína Homeobox Nanog/genética , Antígenos CD/genética , Apoptose/genética , Caderinas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Proteína HMGA2/genética , Humanos , Proteína Homeobox Nanog/metabolismo , Células-Tronco Neoplásicas/patologia , Fator 3 de Transcrição de Octâmero/genética , RNA Interferente Pequeno , Proteínas de Ligação a RNA/genética , Esferoides Celulares/patologia , Transfecção , Vimentina/genética
11.
Nat Commun ; 12(1): 4230, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244494

RESUMO

Extracellular matrix protein-1 (ECM1) promotes tumorigenesis in multiple organs but the mechanisms associated to ECM1 isoform subtypes have yet to be clarified. We report in this study that the secretory ECM1a isoform induces tumorigenesis through the GPR motif binding to integrin αXß2 and the activation of AKT/FAK/Rho/cytoskeleton signaling. The ATP binding cassette subfamily G member 1 (ABCG1) transduces the ECM1a-integrin αXß2 interactive signaling to facilitate the phosphorylation of AKT/FAK/Rho/cytoskeletal molecules and to confer cancer cell cisplatin resistance through up-regulation of the CD326-mediated cell stemness. On the contrary, the non-secretory ECM1b isoform binds myosin and blocks its phosphorylation, impairing cytoskeleton-mediated signaling and tumorigenesis. Moreover, ECM1a induces the expression of the heterogeneous nuclear ribonucleoprotein L like (hnRNPLL) protein to favor the alternative mRNA splicing generating ECM1a. ECM1a, αXß2, ABCG1 and hnRNPLL higher expression associates with poor survival, while ECM1b higher expression associates with good survival. These results highlight ECM1a, integrin αXß2, hnRNPLL and ABCG1 as potential targets for treating cancers associated with ECM1-activated signaling.


Assuntos
Processamento Alternativo , Carcinoma Epitelial do Ovário/genética , Proteínas da Matriz Extracelular/metabolismo , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Ovarianas/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/terapia , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas da Matriz Extracelular/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas/genética , Humanos , Integrina alfaXbeta2/genética , Integrina alfaXbeta2/metabolismo , Estimativa de Kaplan-Meier , Camundongos , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Ovário/patologia , Ovário/cirurgia , Fosforilação/genética , Prognóstico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA-Seq , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200849

RESUMO

Nitric oxide (NO) has been identified and described as a dual mediator in cancer according to dose-, time- and compartment-dependent NO generation. The present review addresses the different epigenetic mechanisms, such as histone modifications and non-coding RNAs (ncRNAs), miRNA and lncRNA, which regulate directly or indirectly nitric oxide synthase (NOS) expression and NO production, impacting all hallmarks of the oncogenic process. Among lncRNA, HEIH and UCA1 develop their oncogenic functions by inhibiting their target miRNAs and consequently reversing the inhibition of NOS and promoting tumor proliferation. The connection between miRNAs and NO is also involved in two important features in cancer, such as the tumor microenvironment that includes key cellular components such as tumor-associated macrophages (TAMs), cancer associated fibroblasts (CAFs) and cancer stem cells (CSCs).


Assuntos
Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/patologia , Células-Tronco Neoplásicas/patologia , Óxido Nítrico/metabolismo , RNA Longo não Codificante/genética , Microambiente Tumoral , Animais , Fibroblastos Associados a Câncer/patologia , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais
13.
Anticancer Res ; 41(7): 3459-3470, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230141

RESUMO

BACKGROUND/AIM: Studies have reported that the expression of c-Met and PrPC improves tumor progression. However, not much is known about their relationship. We hypothesized that c-Met and PrPC interact with each other, and enhance cancer stem cell (CSC) characteristics. MATERIALS AND METHODS: Magnetic activated cell sorting was used to examine the interaction between c-Met and PrPC The effects of the interaction on downstream signals, stem cell marker expression, and sphere formation of colorectal cancer (CRC) cells were investigated. RESULTS: We demonstrated the increased expression and binding levels of c-Met and PrPC in CRC cells compared to normal colon epithelial cells. We revealed that the c-Met and PrPC interaction induced the ERK activation and Oct4 upregulation. The inhibition of c-Met by crizotinib reduced ERK activation and Oct4 expression and suppressed CSC properties. CONCLUSION: c-Met and PrPC interact with each other, and targeting c-Met using crizotinib could be a powerful strategy for CRC therapy.


Assuntos
Neoplasias Colorretais/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas PrPC/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Crizotinibe/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
14.
Anticancer Res ; 41(7): 3689-3698, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230168

RESUMO

BACKGROUND/AIM: SPARC-related modular calcium-binding protein 2 (SMOC2), a secreted matricellular protein, is reported to be involved in cancer progression such as cell cycle, angiogenesis, and invasion. In this study, we aimed to investigate the expression of SMOC2 in various gastric lesions and assessed its prognostic value in a large cohort of gastric cancer (GC) patients. PATIENTS AND METHODS: SMOC2 mRNA levels were measured by quantitative real-time PCR using 26 matched fresh-frozen GC samples. SMOC2 protein expression was determined by immunohistochemistry on tissue microarrays including 734 GC specimens and its correlations with clinicopathological features and survival were evaluated. RESULTS: The transcription level of SMOC2 was higher in GC samples compared to normal mucosa (p=0.006). Its expression levels were associated with the intestinal stem cell (ISC) marker, LGR5, but there were no correlations with EPHB2 and OLFM4 or the candidate cancer stem cell markers CD133 and CD44. SMOC2 expression was significantly increased in the intestinal metaplasia and was further increased in gastric adenomas and early gastric cancers (EGC). In total, 34% of GCs were positive for SMOC2, and SMOC2 positivity was higher in old (p=0.001) and male (p<0.001) patients, and in well-differentiated GC (p<0.001). SMOC2 expression had a negative association with perineural invasion (p<0.001) and tumor stage (p<0.001). In survival analysis, SMOC2-positive GC patients had much better clinical outcomes in overall survival rates (p<0.001) compared to SMOC2-negative GC patients. The prognostic impact of SMOC2 remained significant both in intestinal (p<0.001) and diffuse-type GC (p<0.001). Remarkably, a multivariate analysis demonstrated SMOC2 as an independent prognostic marker [hazard ratio (HR)=0.732, p=0.045] along with venous invasion (p=0.012), tumor stage (p<0.001) and CDX2 (p=0.028). CONCLUSION: Our results suggest that SMOC2 can be a prognostic marker for better clinical outcomes in GC.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/patologia , Células-Tronco Neoplásicas/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Idoso , Feminino , Humanos , Mucosa Intestinal/patologia , Masculino , Estadiamento de Neoplasias/métodos , Células-Tronco Neoplásicas/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
15.
Nat Commun ; 12(1): 3974, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172737

RESUMO

Cancer stem cells (CSCs) play a critical role in invasive growth and metastasis of human head and neck squamous cell carcinoma (HNSCC). Although significant progress has been made in understanding the self-renewal and pro-tumorigenic potentials of CSCs, a key challenge remains on how to eliminate CSCs and halt metastasis effectively. Here we show that super-enhancers (SEs) play a critical role in the transcription of cancer stemness genes as well as pro-metastatic genes, thereby controlling their tumorigenic potential and metastasis. Mechanistically, we find that bromodomain-containing protein 4 (BRD4) recruits Mediators and NF-κB p65 to form SEs at cancer stemness genes such as TP63, MET and FOSL1, in addition to oncogenic transcripts. In vivo lineage tracing reveals that disrupting SEs by BET inhibitors potently inhibited CSC self-renewal and eliminated CSCs in addition to elimination of proliferating non-stem tumor cells in a mouse model of HNSCC. Moreover, disrupting SEs also inhibits the invasive growth and lymph node metastasis of human CSCs isolated from human HNSCC. Taken together, our results suggest that targeting SEs may serve as an effective therapy for HNSCC by eliminating CSCs.


Assuntos
Elementos Facilitadores Genéticos , Neoplasias de Cabeça e Pescoço/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Antineoplásicos/farmacologia , Azepinas/farmacologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Humanos , Metástase Linfática/tratamento farmacológico , Metástase Linfática/prevenção & controle , Subunidade 1 do Complexo Mediador/genética , Subunidade 1 do Complexo Mediador/metabolismo , Camundongos Endogâmicos C57BL , Camundongos SCID , NF-kappa B/genética , Células-Tronco Neoplásicas/patologia , Complexo Repressor Polycomb 1/antagonistas & inibidores , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Triazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Life Sci ; 279: 119667, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34087280

RESUMO

Estimates indicate that cancer will become the leading cause of mortality worldwide in the future. Tumorigenesis is a complex process that involves self-sufficiency in signs of growth, insensitivity to anti-growth signals, prevention of apoptosis, unlimited replication, sustained angiogenesis, tissue invasion, and metastasis. Cancer stem cells (CSCs) have an important role in tumor development and resistance. Here we will approach phenotypic plasticity capacity, highly efficient DNA repair systems, anti-apoptotic machinery, sustained stemness features, interaction with the tumor microenvironment, and Notch, Wnt, and Hedgehog signaling pathways. The researches about CSCs as a target in cancer treatment has been growing. Many different options have pointed beneficial results, such as pathways and CSC-surface markers targeting. Besides its limitations, nanotherapeutics have emerged as a potential strategy in this context since they aim to improve pharmacokinetics, biodistribution, and reduce the side effects observed in traditional treatments. Nanoparticles have been studied in this field, mostly for drug delivery and a multitherapy approach. Another widely researched approaches in this area are related to heat therapy, such as photothermal therapy, photodynamic therapy and magnetic hyperthermia, besides molecular targeting. This review will contemplate the most relevant studies that have shown the effects of nanotherapeutics. In conclusion, although the studies analyzed are mostly preclinical, we believe that there is strong evidence that nanoparticles can increase the chances of a better prognosis to cancer in the future. It is also essential to transpose these findings to the clinic to confirm and better understand the role of nanotherapeutics in this context.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Animais , Antineoplásicos/química , Humanos , Nanopartículas/química , Neoplasias/patologia , Células-Tronco Neoplásicas/patologia
17.
Commun Biol ; 4(1): 718, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112916

RESUMO

Recently, we involved the carbohydrate-binding protein Galectin-3 (Gal-3) as a druggable target for KRAS-mutant-addicted lung and pancreatic cancers. Here, using glioblastoma patient-derived stem cells (GSCs), we identify and characterize a subset of Gal-3high glioblastoma (GBM) tumors mainly within the mesenchymal subtype that are addicted to Gal-3-mediated macropinocytosis. Using both genetic and pharmacologic inhibition of Gal-3, we showed a significant decrease of GSC macropinocytosis activity, cell survival and invasion, in vitro and in vivo. Mechanistically, we demonstrate that Gal-3 binds to RAB10, a member of the RAS superfamily of small GTPases, and ß1 integrin, which are both required for macropinocytosis activity and cell survival. Finally, by defining a Gal-3/macropinocytosis molecular signature, we could predict sensitivity to this dependency pathway and provide proof-of-principle for innovative therapeutic strategies to exploit this Achilles' heel for a significant and unique subset of GBM patients.


Assuntos
Proteínas Sanguíneas/metabolismo , Neoplasias Encefálicas/metabolismo , Galectinas/metabolismo , Glioblastoma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Proteínas Sanguíneas/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Feminino , Galectinas/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Camundongos , Células-Tronco Neoplásicas/patologia , Pinocitose , Mapas de Interação de Proteínas , Transcriptoma , Células Tumorais Cultivadas
18.
ACS Nano ; 15(6): 9967-9986, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34081852

RESUMO

Metastasis is the primary reason for treatment failure and cancer-related deaths. Hence forecasting the disease in its primary state can advance the prognosis. However, existing techniques fail to reveal the tumor heterogeneity or its evolutionary cascades; hence they are not feasible to predict the onset of metastatic cancer. The key to metastasis originates from the primary tumor cells, evolving by inheriting multistep sequential cue signals. We have identified this specific population, termed metastatic cancer stem-like cells (MCSCs), to foresee cancer's ability to metastasize. An invasive property renders MCSCs nonadherent, summoning a powerful technique to forecast metastasis. Thus, we have generated an ultrasensitive 3D-metasensor to efficiently capture and investigate MCSCs and magnify the vital premetastatic signals from a single cell. We developed 3D-metasensor by an ultrafast laser ionization technique, consisting of self-assembled three-dimensionally organized nanoprobes incorporated with dopant functionalities. This distinct methodology establishes attachment with nonadherent MCSCs, elevates Raman activity, and enables probing of consequent signals (metabolic, proliferation, and metastatic) specifically altered in MCSCs. Extensive analysis using prediction tools-the area under the curve (AUC) and principal component analysis (PCA)-revealed high sensitivity (100%) and specificity (80%) to differentiate the MCSCs from other populations. Further, investigation reveals that the cue signal level from MCSCs of primary cancer is analogous to MCSCs from higher-level tumors, disclosing the relative dependence to estimate the primary tumor's capacity to metastasize. Multiple spectrum evaluation using the metasensor pinpoint the dynamic cues in MCSCs predict the onset of metastasis; thus, exploring these metastasis hallmarks can enhance prognosis and revolutionize therapy strategies.


Assuntos
Sinais (Psicologia) , Células-Tronco Neoplásicas , Linhagem Celular Tumoral , Humanos , Metástase Neoplásica/patologia , Células-Tronco Neoplásicas/patologia
19.
Life Sci ; 280: 119729, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34146553

RESUMO

AIMS: To study 5-desmethylsinensetin exhibiting potential anticancer activity against breast cancer stem cells and the related molecular mechanism. MAIN METHODS: In this study, isolation of a cancer stem cell (CSC) inhibitor of Artemisia princeps was performed using a silica gel column, a Sephadex gel column, and high-performance liquid chromatography. A single compound was purified via activity-based isolation using mammosphere formation assays. An MTS was used to examine the proliferation of breast cancer cells, and flow cytometry was used to analyze apoptosis and cancer stem cell markers. Western blotting was used to detect the signaling pathway. RESULTS: The isolated compound was identified as 5-desmethylsinensetin using nuclear magnetic resonance and mass spectrometry. 5-Desmethylsinensetin suppresses the proliferation and mammosphere formation of breast cancer cells, reduces the subpopulations of CD44+/CD24- and ALDH1+ cancer cells, and reduces the transcription of the stemness markers Oct4, c-Myc, Nanog and CD44 in Breast CSCs. 5-Desmethylsinensetin inhibits the total and nuclear expression of Stat3 and p-Stat3, as well as the translocation of YAP1. Additionally, 5-desmethylsinensetin reduces the mRNA and protein levels of IL-6. CONCLUSION: Our results show that 5-desmethylsinensetin exhibits potential anticancer activity against breast cancer stem cells via Stat3-IL-6 and Stat3-YAP1 signaling.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Artemisia , Neoplasias da Mama/tratamento farmacológico , Flavonoides/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Artemisia/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Flavonoides/química , Humanos , Interleucina-6/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fator de Transcrição STAT3/metabolismo , Fatores de Transcrição/metabolismo
20.
J Cancer Res Clin Oncol ; 147(10): 2969-2982, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34170383

RESUMO

PURPOSE: The identification of prognostically and therapeutically relevant molecular markers is fundamental to the further development of personalised therapies in brain tumours. Current therapeutic options for the treatment of gliomas rely mainly on surgical resection and the inhibition of tumour cell proliferation by irradiation and chemotherapy. Glioma stem cells are a subpopulation of proliferating tumour cells that have self-renewal capacity and can give rise to heterogeneous cells that comprise the tumour and are thought to play a role in the resistance of gliomas to therapy. The aim of this study was to evaluate the expression of markers of glioma stem cells and differentiated glial cells in proliferating glioma cells in comparison to the overall expression of the respective markers in the tumour tissue. METHODS: Tissue microarrays were assembled from specimen of pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglioma, anaplastic oligodendroglioma, ependymoma, and anaplastic ependymoma. These were immunohistochemically double stained with antibodies against the proliferation-associated antigen Ki67 and marker proteins for glioma stem cells (CD133, Nestin, Musashi, CD15, CD44), and differentiated glioma cells (GFAP, MAP2c). RESULTS: The expression of both glial and glioma stem cell markers differs between proliferating and non-proliferating glioma cells. Furthermore, the proliferating cells in the different glial tumour entities show a different expression profile. CONCLUSION: Further analysis of marker expression in proliferating glioma cells and correlation with clinical outcome and susceptibility to irradiation and chemotherapy might help establish new biomarkers and therapies for glioma.


Assuntos
Biomarcadores Tumorais/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Células-Tronco Neoplásicas/patologia , Antígeno AC133/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioma/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Antígenos CD15/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Nestina/metabolismo , Proteínas de Ligação a RNA/metabolismo
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